Zebrafish endochondral growth zones as they relate to human bone size, shape and disease

Abstract

Research on the genetic mechanisms underlying human skeletal development and disease have largely relied on studies in mice. However, recently the zebrafish has emerged as a popular model for skeletal research. Despite anatomical differences such as a lack of long bones in their limbs and no hematopoietic bone marrow, both the cell types in cartilage and bone as well as the genetic pathways that regulate their development are remarkably conserved between teleost fish and humans. Here we review recent studies that highlight this conservation, focusing specifically on the cartilaginous growth zones (GZs) of endochondral bones. GZs can be unidirectional such as the growth plates (GPs) of long bones in tetrapod limbs or bidirectional, such as in the synchondroses of the mammalian skull base. In addition to endochondral growth, GZs play key roles in cartilage maturation and replacement by bone. Recent studies in zebrafish suggest key roles for cartilage polarity in GZ function, surprisingly early establishment of signaling systems that regulate cartilage during embryonic development, and important roles for cartilage proliferation rather than hypertrophy in bone size. Despite anatomical differences, there are now many zebrafish models for human skeletal disorders including mutations in genes that cause defects in cartilage associated with endochondral GZs. These point to conserved developmental mechanisms, some of which operate both in cranial GZs and limb GPs, as well as others that act earlier or in parallel to known GP regulators. Experimental advantages of zebrafish for genetic screens, high resolution live imaging and drug screens, set the stage for many novel insights into causes and potential therapies for human endochondral bone diseases.

A Collagen10a1 mutation disrupts cell polarity in a medaka model for metaphyseal chondrodysplasia type Schmid

“…Other than in MCDS, where structural deformities occur in endochondral bones, we expected deformities in both bone and cartilage in col10a1 Δ633a medaka mutants. In line with this, we showed that the ceratohyal bone, which in teleost fish develops via endochondral ossification, 57 was shorter in WT/m col10a1 Δ633a medaka mutants. In addition, cartilaginous structures such as the ceratobranchials and gill filaments were severely deformed in the medaka mutants.…”

The transcriptional state and chromatin landscape of cichlid jaw shape variation across species and environments

“…Each of these genes was upregulated in our study in pelagic foraging MZ compared with benthic foraging conspecifics. Given the well-studied roles for cell proliferation in bone formation, shape and growth (Capecchi et al, 2018;Du et al, 2021;Gao et al, 2020;Le Pabic et al, 2022;Shekhar et al, 2019), the data presented here suggest that this mechanism is important in mediating skeletal plasticity in this species.…”

Dominant nonsense mutations in efemp1 alter vertebral and craniofacial characteristics in adult zebrafish

“…Compared to humans, in zebrafish limited skeletal structures undergo endochondral ossification, whereas a majority of the human skeleton undergoes this process, which could explain some of the differences in efemp1 phenotypes between fish and humans. One location where endochondral ossification occurs in both humans and zebrafish are in the skull and pharyngeal skeleton in the cranium, respectively, which could be why we see changes in craniofacial morphology in both human and zebrafish (Le Pabic et al 2022). Work understanding the potential perturbation of EFEMP1 and ECM1 interaction could broaden our understanding of the skeletal phenotypes in our models and in individuals with EFEMP1 variants.…”